The development of cancer therapeutics rests on finding exploitable differences between cancer cells and normal cells. Treatments such as operative resection and radiation therapy rely on the tumor being localized to an individual site and produce the majority of cancer cures. Systemic therapy, including the use of chemotherapy and biologic therapy, has been successfully applied to some previously untreatable malignancies but unfortunately most patients with metastatic solid tumors cannot be cured by available treatments. The use of biologic therapies, including the systemic administration of individual cytokines and the adoptive transfer of lymphoid cells, has allowed new approaches to some lethal neoplasms such as melanoma and renal cell carcinoma. Unfortunately only a small percentage of patients respond. Gene transfer strategies which either increase the effectiveness of tumor vaccines by incorporating the genes encoding potent cytokines or by increasing the functional capabilities or other features of effector cells are promising new approaches to improve the effectiveness and the range of treatable tumors. We have already begun gene transfer studies with marker genes delivered with retroviral vectors into tumor infiltrating lymphocytes adoptively transferred in conjunction with administration of systemic Interleukin-2 and Interleukin-4. We are now exploring the use of genes delivered with the goal of enhancing the effectiveness of such treatments. Immunological approaches that we are pursuing include the following four projects: 1. IL-4 gene transfection as an approach to increase tumor immunogenicity; 2. IL-12: A novel heterodimeric cytokine for gene therapy to stimulate Immunity and to Enhance Anti-tumor Effector Cell Function; 3. Activated NK cells as vehicles for Gene Therapy; Experimental Models of Human and Murine Tumors and Tumor Metastases; and 4. Constitutive overexpression of protein kinase C genes in antitumor effector cells to facilitate isolation and to potentiate growth and function. these projects as well as three cores (Administrative core, Vector core, and Immunologic Monitoring and Cellular Therapy Core) represent a focused and integrated approach to using gene therapies to enhance the effectiveness of the immunologic treatment of cancer. Collectively this application supports extension of a vigorous, mature program in cancer therapeutics, applying the tools of molecular biology to enhance biologic therapies.